Furyl compounds

ABSTRACT

Compounds of formula I:  
                 
and pharmaceutically-acceptable salts thereof, wherein Ar and R are as defined in the specification, compositions containing such compounds and methods of using such compounds and compositions in therapy.

TECHNICAL FIELD

This invention relates to novel spiroazabicyclic heterocyclic amines orpharmaceutically acceptable salts thereof, processes for preparing them,pharmaceutical compositions containing them and their use in therapy.

BACKGROUND OF THE INVENTION

The use of compounds which bind to nicotinic acetylcholine receptors forthe treatment of a range of disorders involving reduced cholinergicfunction such as Alzheimer's disease, cognitive or attention disorders,anxiety, depression, smoking cessation, neuroprotection, schizophrenia,analgesia, Tourette's syndrome, and Parkinson's disease is discussed inMcDonald et al., (1995) “Nicotinic Acetylcholine Receptors: MolecularBiology, Chemistry and Pharmacology”, Chapter 5 in Annual Reports inMedicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc., San Diego,Calif.; and in Williams et al., (1994) “Neuronal Nicotinic AcetylcholineReceptors,” Drug News & Perspectives, vol. 7, pp. 205-223.

DESCRIPTION OF THE INVENTION

This invention comprises compounds that are potent ligands for nicotinicacetylcholine receptors (nAChR's).

Compounds of the invention are those in accord with formula I:

and pharmaceutically-acceptable salts thereof, wherein:

-   -   Ar is selected from a 2-, or 3-linked furyl, benzofuryl or        isobenzofuryl; substituted with 1, 2 or 3 substitutents, or,        when a benzofuryl or isobenzofuryl with 0, 1, 2, or 3        substituents, independently selected at each occurrence from        C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ halogenated alky, C₁₋₄ oxygenated        alky, C₂₋₄ alkenyl, C₂₋₄alkynyl, halogen, —CO₂R¹, —C(O)R¹, —CN,        —NO₂, —(CH₂)_(n)NR¹R²;    -   n is 0, 1, or 2;    -   R¹ and R² are independently selected at each occurrence from        hydrogen or C₁₋₄ alkyl;    -   R is a substituent selected from hydrogen, C₁₋₄alkyl, C₁₋₄        halogenated alkyl, C₁₋₄ oxygenated alkyl, or halogen.

Particular compounds of the invention are those wherein R is hydrogenand Ar is a 2-, or 3-linked furyl ring bearing a single substituent andsaid substituent is selected from methyl, ethyl, or halogen.

Other particular compounds of the invention are those wherein R ishydrogen and Ar is a 2-, or 3-linked benzofuryl ring which isunsubstituted or bears a single substituent, and said substituent isselected from methyl, ethyl, or halogen.

Particular compounds of the invention include:

-   (2′R)-5′-(benzofuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2R)-5′-(2-bromofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-methylfuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-fluorofuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-methylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-4-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}furan-2-carboxaldehyde;-   (2′R)-5′-(5-hydroxmethylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-4-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}furan-2-carbonitrile;-   (2′R)-5-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}furan-2-carbonitrile;-   (2′R)-5′-(benzofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(2-fluorobenzofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine].

Other particular compounds of the invention include:

-   (2′R)-5′-(5-fluorofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-chlorofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-bromofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′    (3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-trifluoromethylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-aminomethylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-chlorofuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-trifluoromethylfuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(5-aminomethylfuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(2,3-dimethylfuran-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   (2′R)-5′-(2,3-dimethylfuran-5-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine].

In another aspect the invention relates to compounds according toformula I and their use in therapy and compositions containing them.

In a further aspect the invention relates to compounds according toformula I wherein one or more of the atoms is labelled with aradioisotope of the same element. In a particular form of this aspect ofthe invention the compound of formula I is labelled with tritium.

In a particular aspect the invention relates to the use of compoundsaccording to formula I for the therapy of diseases mediated through theaction of nicotinic acetylcholine receptors. A more particular aspect ofthe invention relates to the use of compounds of formula I for thetherapy of diseases mediated through the action of α7 nicotinicacetylcholine receptors.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound as described above, and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the above pharmaceuticalcomposition for use in the treatment of prophylaxis of human diseases orconditions in which activation of the α₇ nicotinic receptor isbeneficial.

Another aspect of the invention relates to the above pharmaceuticalcomposition for use in the treatment or prophylaxis of psychoticdisorders or intellectual impairment disorders.

Another aspect of the invention relates to the above pharmaceuticalcomposition for use in the treatment or prophylaxis of Alzheimer'sdisease, learning deficit, cognition deficit, attention deficit, memoryloss, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia,or mania or manic depression Parkinson's disease, Huntington's disease,Tourette's syndrome, neurodegenerative disorders in which there is lossof cholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,craving, pain, and for ulcerative colitis.

Another aspect of the invention relates to a use of a compound asdescribed above in the manufacture of a medicament for the treatment orprophylaxis of human diseases or conditions in which activation of theα7 nicotinic receptor is beneficial.

Another aspect of the invention relates to a use of a compound asdescribed above in the manufacture of a medicament for the treatment orprophylaxis of psychotic disorders or intellectual impairment disorders.

Another aspect of the invention relates to the above use, wherein thecondition or disorder is Alzheimer's disease, learning deficit,cognition deficit, attention deficit, memory loss, Attention DeficitHyperactivity Disorder.

Another aspect of the invention relates to the above use, wherein thedisorder is anxiety, schizophrenia, or mania or manic depression.

Another aspect of the invention relates to the above use, wherein thedisorder is Parkinson's disease, Huntington's disease, Tourette'ssyndrome, or neurodegenerative disorders in which there is loss ofcholinergic synapses.

Another aspect of the invention relates to the use of a compound asdescribed above in the manufacture of a medicament for the treatment orprophylaxis of jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,craving, pain, and for ulcerative colitis.

Another aspect of the invention relates to a method of treatment orprophylaxis of human diseases or conditions in which activation of theα₇ nicotinic receptor is beneficial which comprises administering atherapeutically effective amount of a compound as described above.

Another aspect of the invention relates to a method of treatment orprophylaxis of psychotic disorders or intellectual impairment disorders,which comprises administering a therapeutically effective amount of acompound as described above.

Another aspect of the invention relates to the above method, wherein thedisorder is Alzheimer's disease, learning deficit, cognition deficit,attention deficit, memory loss, or Attention Deficit HyperactivityDisorder.

Another aspect of the invention relates to the above method, wherein thedisorder is Parkinson's disease, Huntington's disease, Tourette'ssyndrome, or neurodegenerative disorders in which there is loss ofcholinergic synapses.

Another aspect of the invention relates to the above method, wherein thedisorder is anxiety, schizophrenia or mania or manic depression.

Another aspect of the invention relates to a method of treatment orprophylaxis of jetlag, cessation of smoking, nicotine addiction,craving, pain, and for ulcerative colitis, which comprises administeringa therapeutically effective amount of a compound as described above.

A further aspect of the invention relates to a pharmaceuticalcomposition for treating or preventing a condition or disorder asexemplified below arising from dysfunction of nicotinic acetylcholinereceptor neurotransmission in a mammal, preferably a human, comprisingan amount of a compound of formula I, an enantiomer thereof or apharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and an inert pharmaceuticallyacceptable carrier.

For the above-mentioned uses the dosage administered will, of course,vary with the compound employed, the mode of administration and thetreatment desired. However, in general, satisfactory results areobtained when the compounds of the invention are administered at a dailydosage of from about 0.1 mg to about 20 mg/kg of animal body weight.Such doeses may be given in divided doses 1 to 4 times a day or insustained release form. For man, the total daily dose is in the range offrom 5 mg to 1,400 mg, more preferably from 10 mg to 100 mg, and unitdosage forms suitable for oral administration comprise from 2 mg to1,400 mg of the compound admixed with a solid or liquid pharmaceuticalcarrier or diluent.

The compounds of formula I, or an enantiomer thereof, andpharmaceutically acceptable salts thereof, may be used on their own orin the form of appropriate medicinal preparations for enteral orparenteral administration. According to a fer aspect of the invention,there is provided a pharmaceutical composition including preferably lessthan 80% and more preferably less than 50% by weight of a compound ofthe invention in admixture with an inert pharmaceutically acceptablediluent or carrier.

Examples of diluents and carriers are:

-   -   for tablets and dragees: lactose, starch, talc, stearic acid;    -   for capsules: tartaric acid or lactose;    -   for injectable solutions: water, alcohols, glycerin, vegetable        oils;    -   for suppositories: natural or hardened oils or waxes.

There is also provided a process for the preparation of such apharmaceutical composition which comprises mixing the ingredients.

A further aspect of the invention is the use of a compound according tothe invention, an enantiomer thereof or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for the treatment orprophylaxis of one of the below mentioned diseases or conditions; and amethod of treatment or prophylaxis of one of the above mentioneddiseases or conditions, which comprises administering a therapeuticallyeffective amount of a compound according to the invention, or anenantiomer thereof or a pharmaceutically acceptable salt thereof, to apatient.

Compounds according to the invention are agonists of nicotinicacetylcholine receptors. While not being limited by theory, it isbelieved that agonists of the α7 nAChR (nicotinic acetylcholinereceptor) subtype should be useful in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders, and haveadvantages over compounds which are or are also agonists of the α4 nAChRsubtype. Therefore, compounds which are selective for the α7 nAChRsubtype are preferred. The compounds of the invention are indicated aspharmaceuticals, in particular in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders. Examples ofpsychotic disorders include schizophrenia, mania and manic depression,and anxiety. Examples of intellectual impairment disorders includeAizheimer's disease, learning deficit, cognition deficit, attentiondeficit, memory loss, and Attention Deficit Hyperactivity Disorder. Thecompounds of the invention may also be useful as analgesics in thetreatment of pain (including chronic pain) and in the treatment orprophylaxis of Parkinson's disease, Huntington's disease, Tourette'ssyndrome, and neurodegenerative disorders in which there is loss ofcholinergic synapses. The compounds may further be indicated for thetreatment or prophylaxis of jetlag, for use in inducing the cessation ofsmoking, craving, and for the treatment or prophylaxis of nicotineaddiction (including that resulting from exposure to products containingnicotine).

It is also believed that compounds according to the invention are usefulin the treatment and prophylaxis of ulcerative colitis.

As used herein, the term “C₁₋₄ alkyl” refers to a straight-chained,branched, or cyclic C₁₋₄alkyl group.

As used herein the term “C₁₋₄ halogenated alkyl” refers to a C₁₋₄alkylgroup substituted with 1, 2, or 3 halogen atoms.

As used herein the term “C₁₋₄ oxygenated allyl” refers to a C₁₋₄hydroxyalkyl or C₁₋₄ alkoxyalkyl group.

Methods of Preparation

Methods which may be used for the synthesis of compounds of formula Iinclude the method outlined in Scheme 1. Unless otherwise noted Ar and Rin Scheme 1 are as defined above for Formula 1.

Compounds of formula I may be prepared from compounds of formula IIwherein X represents a halogen or OSO₂CF₃ substituent by reaction withan appropriate organometallic compound of formula III in the presence ofa suitable organometallic catalyst and solvent. Suitable compounds offormula III include boronic acids, in which M represents B(OH)₂, boronicacid esters, in which M represents B(OY)₂, where Y represents a suitableacyclic or cyclic alkyl or aryl group, and organotin compounds, in whichM represents a suitable trialkylstannyl group, for exampletrimethylstannyl or tri-n-butylstannyl. Suitable organometalliccatalysts include palladium (0) complexes, for exampletetrakis(triphenylphosphine)palladium(0) or a combination oftris(dibenzylideneacetone)dipalladium(0) and a suitable triarylphosphineor triarylarsine ligand, for example triphenylphosphine,tri(o-tolyl)phosphine or triphenylarsine. Suitable solvents includeinert ether solvents, for example 1,2-dimethoxyethane, tetrahydrofaran,or 1,4-dioxane, or alcohols, such as ethanol, or mixtures thereof. Ifthe compound of formula III is a boronic acid, the presence of asuitable base in addition to the other reagents is preferred. Suitablebases include sodium carbonate, cesium carbonate, and barium hydroxide.The reaction is carried out at a temperature of 0-120° C., andpreferably at a temperature of 60-120° C.

Certain compounds of formula II wherein X represents halogen may beprepared from compounds of formula II wherein X represents hydrogen byreaction with a suitable halogenating agent in a suitable solvent.Suitable halogenating agents include bromine. Suitable solvents includeacetic acid. The reaction is preferably performed at a temperature of0-50° C., and most preferably at a temperature of 0-25° C. Compounds offormula II may be prepared by the methods described in applicationWO99/03859.

Compounds of formula II wherein X represents OSO₂CF₃ may be preparedfrom compounds of formula II wherein X represents OH by reaction withtrifluoromethanesulfonic anhydride or othertrifluoromethanesulfonylating agent in the presence of a base and asuitable solvent. Suitable bases include pyridine, and2,6-di-t-butylpyridine. The reaction is preferably performed at atemperature of −78 to 120° C., and most preferably at a temperature of−78 to 0° C.

Compounds of formula III are commercially available, are described inthe literature of synthetic organic chemistry, or may be prepared bymethods known to one skilled in the art of synthetic organic chemistry.For example, compounds of formula M in which M represents B(OH)₂ may beprepared from suitable aromatic compounds having hydrogen or halogengroups, via conversion to the corresponding aryllithium or arylmagnesiumcompounds followed by reaction with trialkyllborate and subsequenthydrolysis of the resulting borate ester. Similarly, suitable aromaticcompounds having hydrogen or halogen groups may be converted tocompounds of formula III in which M represents a trialkylstannyl groupvia conversion to the corresponding aryllithium or arylmagnesiumcompounds followed by reaction with an appropriate trialkylstannylhalide. The formation of the aryllithium or arylmagnesium compound isperformed in a suitable inert solvent, for example, tetrahydrofuran.Alternatively, suitable aromatic compounds having halogen or OSO₂CF₃ maybe converted to compounds of formula III in which M represents B(OH)₂via reaction with bis(pinacolato)diboron and an organometallic catalyst,followed by hydrolysis of the resulting borate ester, or to compounds offormula III in which M represents a trialkylstannyl group via reactionwith the appropriate bis(trialkyltin) in the presence of a suitableorgnometallic catalyst. The reaction is performed in a suitable inertsolvent, for example tetrahydrofuran, and suitable organometalliccatalyst include, for example tetrakis(triphenylphosphine). The reactionis performed at a temperature of about 0° C. to about 150° C.,preferably about 20° C. to about 100° C. For typical procedures foreffecting such conversions, see, for example, Organic Syntheses, 1963,Coll Vol. 4, 68; J. Org. Chem. 1995, 60, 7508.

An alternative synthesis of compounds of formula I is outlined in Scheme2. Unless otherwise noted Ar, R, M and X in Scheme 2 are as definedabove for Scheme 1, and Ar and R are as defined in Formula I. Theconditions for effecting the preparation described in Scheme 2 would besimilar to those under which the preparations described in Scheme 1would be performed with corresponding M and X groups.

Compounds of formula IV in which M represents B(OH)₂ may be preparedfrom compounds of formula II in which X is halogen, via conversion tothe corresponding aryllithium or arylmagnesium compounds followed byreaction with trialkylborate and subsequent hydrolysis of the resultingborate ester. Similarly, compounds of formula IV in which M representsSnR³ ₃ and R³ represents a C₁-C₆ alkyl group may be prepared fromcompounds of formula II in which X is halogen, via conversion to thecorresponding aryllithium or arylmagnesium compounds followed byreaction with an appropriate trialkylstannyl halide. The formation ofthe aryllithium or arylmagnesium compound is performed in a suitableinert solvent, for example, tetrahydrofuran, and Alternatively,compounds of formula IV in which M represents B(OH)₂ may be preparedfrom compounds of formula II in which X represents halogen or OSO₂CF₃via reaction with bis(pinacolato)diboron and an organometallic catalyst,followed by hydrolysis of the resulting borate ester, and compounds offormula IV in which M represents represents SnR³ ₃ and R³ represents aC₁-C₆ alkyl group may be prepared from compounds of formula II in whichX represents halogen or OSO₂CF₃ via reaction with the appropriatebis(trialkyltin) R³ ₃SnSnR³ ₃ in the presence of a suitableorgnometallic catalyst. The reaction is performed in a suitable inertsolvent, for example tetrahydrofuran, and suitable organometalliccatalyst include, for example tetrakis(triphenylphosphine). The reactionis performed at a temperature of about 0° C. to about 150° C.,preferably about 20° C. to about 100° C. For typical procedures foreffecting such conversions, see, for example, Organic Syntheses, 1963,Coll. Vol. 4, 68; J. Org. Chem. 1995, 60, 7508.

A further aspect of the invention therefore relates to intermediates.Such intermediates are useful in the synthesis of compounds of formulaI, and other compounds that bind nicotinic acetylcholine receptors.Particularly useful intermediates are compounds of formula IV below:

wherein:

-   M represents B(OH)₂, B(OR³)₂ or SnR³ ₃;-   R is a substitutent selected from hydrogen, C₁₋₄alkyl, C₁₋₄    halogenated alkyl, C₁₋₄ oxygenated alkyl, or halogen;-   R³ represents a C₁-C₆ alkyl group.

Particular compounds that are useful intermediates include:

-   (2′R)-5′-trimethylstannyl-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine].

It will be appreciated by one skilled in the art that certain optionalaromatic substituents in the compounds of the invention may beintroduced by employing aromatic substitution reactions, or functionalgroup transformations to modify an existing substituent, or acombination thereof. Such reactions may be effected either prior to orimmediately following the processes mentioned above, and are included aspart of the process aspect of the invention. The reagents and reactionconditions for such procedures are known in the art. Specific examplesof procedures which may be employed include, but are not limited to,electrophilic functionalisation of an aromatic ring, for example vianitration, halogenation, or acylation; transformation of a nitro groupto an amino group, for example via reduction, such as by catalytichydrogenation; acylation, alkylation, sulfonylation of an amino orhydroxyl group; replacement of an amino group by another functionalgroup via conversion to an intermediate diazonium salt followed bynucleophilic or free radical substitution of the diazonium salt; orreplacement of a halogen by another functional group, for example vianucleophilic or organometallically-catalysed substitution reactions.

Where necessary, hydroxy, amino, or other reactive groups may beprotected using a protecting group as described in the standard text“Protecting groups in Organic Synthesis”, 3^(rd) Edition (1999) byGreene and Wuts.

The above-described reactions, unless otherwise noted, are usuallyconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere).

Unless otherwise stated, the above-described reactions are conductedunder an inert atmosphere, preferably under a nitrogen atmosphere.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures by standard techniques.

Acid addition salts of the compounds of formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate, tartrate, and fumarate salts. Acid additionsalts of compounds of formula I may be formed by reacting the free baseor a salt, enantiomer or protected derivative thereof, with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, e.g., water, dioxane, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved in vacuum or by freeze drying. The reaction may be ametathetical process or it may be carried out on an ion exchange resin.

The compounds of formula I and IV exist in tautomeric or enantiomericforms, all of which are included within the scope of the invention. Thevarious optical isomers may be isolated by separation of a racemicmixture of the compounds using conventional techniques, e.g. fractionalcrystallisation, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions which will not causeracemisation.

Pharmacology

The pharmacological activity of compounds of the invention may bemeasured using the tests set out below:

Test A—Assay for Affinity at α7 nAChR Subtype

[¹²⁵I]α-Bungarotoxin (BTX) binding to rat hippocampal membranes. Rathippocampi were homogenized in 20 volumes of cold homogenization buffer(HB: concentrations of constituents (mM):tris(hydroxymethyl)aminomethane 50; MgCl₂ 1; NaCl 120; KCl 5: pH 7.4).The homogenate was centrifuged for 5 minutes at 1000 g, the supernatantwas saved and the pellet re-extracted. The pooled supernatants werecentrifuged for 20 minutes at 12000 g, washed, and resuspended in HB.Membranes (30-80 μg) were incubated with 5 nM [¹²⁵I]α-BTX, 1 mg/mL BSA(bovine serum albumin), test drug, and either 2 mM CaCl₂ or 0.5 mM EGTA[ethylene glycol-bis(β-aminoethylether)] for 2 hours at 21° C., and thenfiltered and washed 4 times over Whatman glass fibre filters (thicknessC) using a Brandel cell harvester. Pretreating the filters for 3 hourswith 1% (BSA/0.01% PEI (polyethyleneimine) in water was critical for lowfilter blanks (0.07% of total counts per minute). Nonspecific bindingwas described by 100 μM (−)-nicotine, and specific binding was typically75%.

Test B—Assay for Affinity to the α4 nAChR Subtype

[³H]-(−)-nicotine binding. Using a procedure modified fromMartino-Barrows and Kellar (Mol Pharm (1987) 31:169-174), rat brain(cortex and hippocampus) was homogenized as in the [¹²⁵I]α-BTX bindingassay, centrifuged for 20 minutes at 12,000×g, washed twice, and thenresuspended in HB containing 100 μM diisopropyl fluorophosphate. After20 minutes at 4° C., membranes (approximately 0.5 mg) were incubatedwith 3 nM [³H]-(−)-nicotine, test drug, 1 μM atropine, and either 2 mMCaCl₂ or 0.5 mM EGTA for 1 h at 4° C., and then filtered over Whatmanglass fiber filters (thickness C) (pretreated for 1 h with 0.5% PEI)using a Brandel cell harvester. Nonspecific binding was described by 100μM carbachol, and specific binding was typically 84%.

Binding Data Analysis for Tests A and B

IC₅₀ values and pseudo Hill coefficients (nH) were calculated using thenon-linear curve-fitting program ALLFIT (DeLean A, Munson P J andRodbard D (1977) Am. J. Physiol., 235:E97-E102). Saturation curves werefitted to a one site model, using the non-linear regression programENZFITTER (Leatherbarrow, R. J. (1987)), yielding KD values of 1.67 and1.70 nM for the [¹²⁵I]-α-BTX and [3H]-(−)-nicotine ligands respectively.Ki values were estimated using the general Cheng-Prusoff equation:Ki-[IC₅₀]/((2+([ligand]/[KD])n)l/n−1)where a value of n=1 was used whenever nH<10.5 and a value of n=2 wasused when nH≧1.5. Samples were assayed in triplicate and were typically±5%. Ki values were determined using 6 or more drug concentrations. Thecompounds of the invention are compounds with binding affinities (Ki) ofless than 1000 nM in either Test A or Test B, indicating that they areexpected to have useful therapeutic activity.

The compounds of the invention have the advantage that they may be lesstoxic, be more efficacious, be longer acting, have a broader range ofactivity, be more potent, produce fewer side effects, are more easilyabsorbed or have other useful pharmacological properties.

EXAMPLES

Commercial reagents were used without further purification.n-Butyllithium was used as a solution in hexane. Mass spectra wererecorded using an HPLC-MS system employing an HP-1100 HPLC and aMicromass LCZ Mass Spectrometer using APCI as the ionisation technique,an an HPLC-MS system employing an HP-1100 HPLC and an HP-1100-seriesmass selective detector using APCI as the ionisation technique, or aGC-MS system employing an HP-6890 gas chromatograph and an HP-5973 massselective detector employing electron impact ionisation, and arereported as m/z for the parent molecular ion. Room temperature refers to20-25° C.5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and other precursors were prepared as described in international patentapplication WO 99/03859. Radiolabelled forms of compounds of theexamples are useful in a screen for the discovery of novel medicinalcompounds which bind to and modulate the activity, via agonism, partialagonism, or antagonism, of the α7 nicotinic acetylcholine receptor. Suchradiolabelled compounds are synthesized either by incorporatingradiolabelled starting materials or, in the case of tritium, exchange ofhydrogen for tritium by known methods. Known methods include (1)electrophilic halogenation, followed by reduction of the halogen in thepresence of a tritium source, for example, by hydrogenation with tritiumgas in the presence of a palladium catalyst, or (2) exchange of hydrogenfor tritium performed in the presence of tritium gas and a suitableorganometallic (e.g. palladium) catalyst.

Preparation 1

(2′R)-5′-(Furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furor[2,3-b]pyridine]

(2′R)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](0.70 g, 2.37 mmol), 3-furylboronic acid (0.39 g, 3.5 mmol),tetrakis(triphenylphosphine)palladium (0) (131 mg, 0.11 mmol), andsodium carbonate (0.75 g, 7.1 mmol) were placed in a tube undernitrogen. Water (3 mL), ethanol (3 mL) and tetrahydrofuran (12 mL) wereadded. The mixture was then heated at 70° C. and stirred under nitrogenfor 24 h. The mixture was then evaporated under vacuum and the residuefrom evaporation was partitioned between dilute aqueous sodium hydroxideand chloroform, the layers were separated, and the aqueous layer wasfurther extracted with chloroform. The chloroform extract was dried(magnesium sulfate), filtered, and evaporated. The residue was purifiedby reverse phase HPLC on a Waters Novapak-HR C₁₈ Column using a gradientof 0-70% acetonitrile/water (each solvent containing 0.1%trifluoroacetic acid as a buffer) as the eluant. The product-containingfractions were evaporated, then the residue was dissolved in methanol.Excess concentrated hydrochloric acid was added, and the solution wasevaporated to give the dihydrochloride salt of the title compound (489mg) as a colourless solid; m.p. 223-225° C. (decomp.); m/z 283 (100%,MH⁺).

Example 1(2′R)-5′-(Benzofuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by a method analogous to that described for the preparation of(2′R)-5′-(furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]in Preparation 1 from(2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and benzofuran-2-boronic acid. The compound was purified by flashchromatography using a gradient of ammoniated methanol in chloroform andobtained as a pale solid; m/z 333 (100%, MH⁺).

Example 2(2′R)-5′-(2-Bromofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(2′R)-5′-(Furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](102 mg, 0.37 mmol), was stirred with bromine (65 mg, 0.41 mmol) in DMF(3 ml) at room temperature for 1 h. Vaccum was applied, and the mixturewas stirred for a further 30 min. The reaction mixture was diluted withchloroform, and washed with aqueous sodium hydroxide, then the organiclayer was dried, filtered and evaporated. The compound was purified byflash chromatography using a gradient of ammoniated methanol inchloroform to give the title compound (28 mg) as a pale solid; m/z 361,363 (MH⁺).

Example 3(2′R)-5′-(5-Metlylfuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by a method analogous to that described for the preparation of(2′R)-5′-(furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]in Preparation 1 from(2′R)-5′-bromo-spiro[1-azabicyclo[2.2.2)octane-3,2′(3′H)-furo[2,3-b]pyridine]and 5-methylfuran-2-boronic acid. The title compound was obtained as acolourless solid; m/e 297 (MH⁺).

Example 4(2′R)-5′-(5-Fluorofuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(a) 5-Fluoro-2-tri-n-butylstannylfuran

5-Bromo-2-furoic acid (300 mg, 1.57 mmol) and sodium bicarbonate (316mg, 3.76 mmol) was stirred in 3.5 mL of pentane/water (2:5) at roomtemperature for 5 minutes.1-Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis-(tetrafluoroborate (“Selectfluor®”) (668 mg, 1.88 mmol) was added,and the mixture was stirred for another hour at room temperature. Thepentane layer containing 5-bromo-2-fluorofuran was separated from themixture, dried (MgSO₄), and used for next step directly. The pentanesolution of 5-bromo-2-fluorofuran was diluted with 3 mL of anhydrousether, and cooled to −78° C. under nitrogen. n-Butyllithium (1.6M, 0.25mL, 0.39 mmol) was added, and the solution was stirred at −78° C. for 10minutes. Tri-n-butylstannyl chloride (127 mg, 0.39 mmol) then was added,and the solution was allowed to warm to room temperature, and stirredfor another 20 minutes. The mixture was quenched and washed with 1Nsodium hydroxide, then the organic layer was separated, dried throughMgSO₄, and filtered, and then the solvent was evaporated to give thesub-title compound (155 mg) as a brown oil which was used withoutfurther purification for the next step.

(b)(2′R)-5′-(5-Fluorofuran-2-yl)spiror[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furor2.3-b]pyridine]

(2′R)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](80 mg, 0.27 mmol), 2-tri-n-butylstannyl-5-fluorofuran (102 mg, 0.27mmol) and tetrakis(triphenylphosphine)palladium (0) (32 mg, 0.027 mmol)were mixed with 1 mL of toluene and sealed under nitrogen. The mixturewas stirred and heated at 120° C. under nitrogen for 2 h. The mixturewas then allowed to cool, and filtered through diatomaceous earth. Thefiltrate was diluted with chloroform, washed with saturated sodiumbicarbonate, dried through MgSO₄, filtered, and then the solvent wasevaporated. The compound was purified by flash chromatography using agradient of ammoniated methanol in chloroform followed by reverse phaseHPLC on a Waters Novapak-HR Cl₈ Column using a gradient of 0-65%acetonitrile/water (each solvent containing 0.1% trifluoroacetic acid asa buffer) as the eluant. The product-containing collections wereevaporated. The residue was dissolved in methanol, then excess 1Nhydrochloric acid was added, and the solvent was evaporated to give thedihydrochloride salt of the title compound (40 mg) as a colourlesssolid; m/e 301 (MH⁺).

Example 5(2′R)-5′-(5-Methylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(a)(2′R)-5′-Trimethylstannyl-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(2′R)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](690 mg, 2.34 mmol), hexamethylditin (1.225 g, 0.27 mmol) andtetrakis(triphenylphosphine)palladium (0) (266 mg, 0.027 mmol) weremixed with 10 mL of toluene and sealed under nitrogen. The mixture wasstirred and heated at 120° C. under nitrogen for 4 h. The mixture wasthen allowed to cool and filtered through diatomaceous earth. Thefiltrate was diluted with chloroform, washed with saturated sodiumbicarbonate, dried through MgSO₄, filtered, and then the solvent wasevaporated. Purification by flash chromatography using a gradient ofammoniated methanol in chloroform gave the sub-title compound as a palesolid (780 mg); m/e 377 379 381 (M⁺). The compound was used in step (c)without further purification.

(b) 4-Bromo-2-methylfuran

4-Bromo-2-furaldehyde (220 mg, 1.26 mmol) and hydrazine (161 mg, 5.03mmol) were stirred in 3 mL of anhydrous ether at room temperature for 5minutes. Then calcium chloride (168 mg, 1.51 mmol) was added, and themixture was stirred for 1 h. The mixture was filtered, and the filtratewas evaporated. The residue was dissolved in 2 mL of anhydrous ethanol,and sodium ethoxide (685 mg, 10.1 mmol) was added. The reaction washeated at 90° C. for 2 h. The mixture was diluted with a large amount ofwater, and extracted with pentane. The organic layer was washed withwater and brine, and dried through MgSO₄. Because the product was veryvolatile, the product-containing solution was used for step (c) withoutevaporation of further purification; m/e 160, 162 (M+).

(c)(2′R)-5′-(5-Methylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(2′R)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](125 mg, 0.23 mmol), 4-bromo-2-methyl-furan (1.2 mL of the solution fromstep (b) above) and tetrakis(triphenylphosphine)palladium (0) (23 mg,0.02 mmol) were mixed with 2 mL of toluene and sealed under nitrogen.The mixture was stirred and heated at 120° C. for 2 h under nitrogen.The mixture was filtered through diatomaceous earth. The filtrate wasdiluted with chloroform, washed with saturated sodium bicarbonate, driedthrough MgSO₄, filtered, and then the solvent was evaporated. Thecompound was purified by flash chromatography followed by reverse phaseHPLC on a Waters Novapak-HR C₁₈ Column using a gradient of 0-65%acetonitrile/water (each solvent containing 0.1% trifluoroacetic acid asa buffer) as the eluant. The product-containing collections wereevaporated. The residue was dissolved in methanol, then excess 1Nhydrochloric acid was added, and the solvent was evaporated to give thedihydrochloride salt of the title compound (3 mg) as a colourless solid;m/e 297 (MH⁺).

Example 6(2′R)-4-{Spiro[1-azabicyclo[2.2.2]octane-3.2′(3′H)-furo[2,3-b]pyridin-5′-yl}furan-2-carboxaldehyde

Prepared by a method analogous to that described for the preparation ofExample 5 from(2′R)-5′-trimethylstannylspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and 4bromo-2-furaldehyde and purified by flash chromatography using agradient of ammoniated methanol in chloroform the title compound as abrown oil; m/e 311 (MH⁺).

Example 7(2′R)-5′-(5-Hydroxmethylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(2′R)-4-{Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}furan-2-carboxaldehyde(180 mg, 0.41 mmol), and CeCl₃ (181 mg, 0.49 mmol) were stirred in 2 mLof ethanol at room temperature for 30 min. The solution was cooled to 0°C. and sodium borohydride (62 mg, 1.64 mmol) was added, and stirring wascontinued at 0° C. for 2 h. The mixture was diluted with a large amountof chloroform, and then washed with saturated sodium bicarbonate, driedthrough MgSO₄, filtered, and then the solvent was evaporated. Afterflash chromatography using a gradient of ammoniated methanol inchloroform the title compound (64 mg) was obtained as a pale solid; m/e313 (MH⁺).

Example 8(2′R)-4-{Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furor[2,3-b]pyridin-5′-yl}furan-2-carbonitrile

(a) 4-Bromofuran-2-carbonitrile

4-Bromofuran-2-carboxaldehyde (3.70 g, 21.15 mmol) was dissolved in 150mL of methanol/dichloromethane (1:4 by volume). Pyridine (3.4 mL, 42.30mmol) and hydroxylamine hydrochloride (1.50 g, 21.15 mmol) were addedsequentially. The mixture was stirred at room temperature. After 2 h,the solvent was evaporated from the reaction mixture. The residue wasdissolved in dichloromethane (180 mL), and pyridine (3.4 mL, 42.30 mmol)was added. The mixture was cooled to 0° C., then phenylphosphonicdichloride (8.46 g, 42.30 mmol) was added. The reaction mixture was thenallowed to warm to room temperature and stirred overnight. The reactionmixture was then washed with saturated sodium bicarbonate, water, andbrine. The organic layer was dried through MgSO₄, and then the solventwas evaporated. Flash chromatography using a gradient of ammoniatedmethanol in chloroform as the eluant gave the sub-title compound (2.85g) as a pale-yellow solid.

(b) 4-Tri-n-butylstanylfuran-2-carbonitrile

n-Butyllithium (1.6M, 3.7 mL, 5.93 mmol) was added to a solution of4-bromofuran-2-carbonitrile (850 mg, 4.94 mmol) in anhydrous ether (15mL) stirred at −78° C. under nitrogen. After 10 min, tri-n-butylstannylchloride (1.61 g, 4.94 mmol) was added, then the reaction mixture wasallowed to warm to room temperature, and stirred for another 1 h. Themixture was quenched, and washed with 1N sodium hydroxide, dried throughMgSO₄, and then the solvent was evaporated to give a brown oily residue.Purification by flash chromatography using a gradient of ammoniatedmethanol in chloroform gave the sub-title compound as a yellow oil (1.0g).

(c)(2′R)-4-{Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furor[2,3-b]pyridin-5′-yl}furan-2-carbonitrile

Method A

Prepared by a method analogous to that described for the preparation ofExample 5 from (2′R)-5′-trimethylstannyl-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and4-bromofuran-2-carbonitrile. The title compound was obtained as acolourless solid; m/e 308 (MH⁺).

Method B

Prepared by a method analog to that described for the preparation ofExample 4 from(2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and 4-tri-n-butylstannylfuran-2-carbonitrile.

Example 9(2′R)-5-{Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}furan-2-carbonitrile

(a) 5-Bromofuran-2-carbonitrile

Prepared by a method analogous to that described above for thepreparation of 4-bromofuran-2-carbonitrile from5-bromofuran-2-carboxaldehyde and obtained as a brown oil.

(b)(2′R)-5-{Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}furan-2-carbonitrile

Prepared by a method analog to that described for the preparation ofExample 5 from(2′R)-5′-trimethylstannyl-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and 5-bromofuran-2-carbonitrile. The title compound was obtained as acolourless solid; m/e 308.3 (MH⁺).

Example 10(2′R)-5′-(Benzofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pridine]

(a) 3-Tri-n-butylstannylbenzofuran

A solution of bromine (4.49 g, 28.09 mmol) in chloroform (5 mL), wasadded slowly to a stirred mixture of benzofuran (1.58 g, 13.38 mmol) andpotassium acetate (2.69 g, 27.42 mmol) in chloroform (20 mL) at roomtemperature. After the addition was complete, the reaction mixture waswarmed to 50° C. and stirred at this temperature for 5 h. The solutionwas then allowed to cool, and washed with 5% NaHSO₃, then brine, thendried through MgSO₄, filtered and evaporated to givetrans-2,3-dihydro-2,3-dibromo-benzofuran as a pale-yellow solid (2.88g). The pale-yellow solid (2.18 g, 7.84 mmol) was dissolved in anhydrousethanol (20 mL) then sodium ethoxide (1.33 g, 19.60 mmol) was added andthe resulting mixture was heated to 50° C. and stirred at thistemperature for 5 h. The solution was allowed to cool, then brine added,and the solution was extracted with ether. The ether layer was washedwith water and brine, dried through MgSO₄, and the solvent wasevaporated to give a brown oily residue. Purification by flashchromatography using a gradient of ammoniated methanol in chloroformgave 3-bromo-benzofuran as a light-brown oil (1.50 g). Under nitrogen,the 3-bromobenzofuran (450 mg, 2.28 mmol) was then dissolved inanhydrous ether, (10 mL) and stirred at −78° C. n-Butyllithium (1.6M,2.3 mL, 3.65 mmol) was added, and stirring was continued at −78° C.After 15 min, tri-n-butylstannyl chloride (668 mg, 2.05 mmol) was added,then the solution was allowed to warm to room temperature, and stirringwas continued for another 1 h. The mixture was quenched, and washed with1N sodium hydroxide, dried through MgSO₄, and then the solvent wasevaporated to give a brown oily residue. Purification by flashchromatography using a gradient of ammoniated methanol in chloroform asthe eluant gave the sub-title compound as a yellow oil (570 mg).

(b)(2′R)-5′-(Benzofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by a method analogous to that described for the preparation ofExample 4 from(2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and 3-tri-n-butylstannylbenzofuran. The title compound was obtained as acolourless solid; m/e 333 (MH⁺).

Example 11(2′R)-5′-(2-Fluorobenzofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(a) 2-Fluoro-3-triethylstannyl-benzofuran

Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis-(tetrafluoroborate (“Selectfluor®”) (13.11 g, 37.01 mmol) was addedto a mixture of benzofuran-2-carboxylic acid (5.0 g, 30.84 mmol) andsodium bicarbonate (6.22 g, 74.0 mmol) stirred in 70 mL of pentane/water(2:5 by volume) at room temperature. After 1 hour at the pentane layercontaining 2-fluorobenzofuran was separated from the mixture, and thewater layer was extracted with pentane. The combined organic extract wasdried through MgSO₄, and then the solvent was evaporated to give2-fluorobenzofuran (1.70 g) as a yellow oil. The 2-fluorobenzofuran (850mg, 6.24 mmol) and potassium acetate (1.29 g, 13.11 mL) were stirred inof chloroform (3.5 mL) at room temperature, and a solution of bromine(2.05 g, 12.80 mmol) in of chloroform (1 mL), and added slowly into thereaction mixture. After stirring for 1 h at room temperature, themixture was washed with 5% NaHSO₃ then brine, dried through MgSO₄, andthe solvent was evaporated to givetrans-2-fluoro-3-hydro-2,3-dibromo-benzofuran as a light-brown oil (1.70g). trans-2-Fluoro-3-hydro-2,3-dibromo-benzofuran (1.66 g, 5.62 mmol)was dissolved in anhydrous ethanol (11 mL), and sodium ethoxide (420 mg,6.18 mmol) was added. The mixture was stirred at RT for 5 min then brinewas added, and the solution was extracted with pentane. The pentanelayer was washed with water and with brine, dried through MgSO₄, andthen the solvent was evaporated to give 3-bromo-2-fluorobenzofuran as alight-brown oil (950 mg). Under nitrogen, 3-bromo-2-fluorobenzofuran(465 mg, 2.16 mmol) was dissolved in anhydrous ether (5 mL), and stirredat −78° C. under nitrogen. n-Butyllithium (1.6M, 1.50 mL, 2.38 mmol) wasadded followed after 5 min by triethylstannyl bromide (680 mg, 2.38mmol). The mixture was then allowed to warm to room temperature andstirring was continued for a further 1 h. The mixture was quenched, andwashed with 1N sodium hydroxide, dried through MgSO₄, and then thesolvent was evaporated to give the sub-title compound as a brown oil(370 mg), which was used directly without further purification for thenext step.

(b)(2′R)-5′-(2-Fluorobenzofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by a method analogous to that described for the preparation ofExample 4 from(2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and 2-fluoro-3-triethylstannylbenzofuran. The title compound wasobtained as a colourless solid; m/e 351 (MH⁺).

1. A compound having the formula:

and pharmaceutically-acceptable salts thereof, wherein Ar is selectedfrom a 2-, or 3-linked furyl, benzofuryl or isobenzofuryl; substitutedwith 1, 2 or 3 substitutents, or, when a benzofuryl or isobenzofurylwith 0, 1, 2, or 3 substituents, independently selected at eachoccurrence from C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ halogenated alkyl,C₁₋₄oxygenated alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halogen, —CO₂R¹,—C(O)R¹, —CN, —NO₂, —(CH₂)_(n)NR¹R²; n is 0, 1, or 2; R¹ and R² areindependently selected at each occurrence from hydrogen or C₁₋₄alkyl; Ris a substituent selected from hydrogen, C₁₋₄alkyl, C₁₋₄ halogenatedalkyl, C₁₋₄ oxygenated alkyl, or halogen.
 2. A compound according toclaim 1 or a pharmaceutically-acceptable salt thereof, wherein: Ar is a2-, or 3-linked furyl ring bearing a single substituent and saidsubstituent is selected from methyl, ethyl, or halogen, and R ishydrogen.
 3. A compound according to claim 1, selected from:(2′R)-5′-(benzofuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(2-bromofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-methylfuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-fluorofuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-methylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-4-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-ylfuran-2-carboxaldehyde;(2′R)-5′-(5-hydroxmethylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(31′H)-furo[2,3-b]pyridine];(2′R)-4-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}furan-2-carbonitrile;(2′R)-5-{spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridin-5′-yl}furan-2-carbonitrile;(2′R)-5′-(benzofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(2-fluorobenzofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-fluorofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-chlorofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-bromofuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-trifluoromethylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-aminomethylfuran-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-chlorofuran-2-yl)spiro1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-trifluoromethylfuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(5-aminomethylfuran-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];(2′R)-5′-(2,3-dimethylfuran-4-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine],or(2′R)-5′-(2,3-dimethylfuran-5-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine].4. A pharmaceutical composition comprising a compound according to claim1, and a pharmaceutically-acceptable diluent or carrier. 5-13.(canceled)
 14. A method of treatment or prophylaxis of human diseases orconditions in which activation of the α₇ nicotinic receptor isbeneficial which comprises administering a therapeutically effectiveamount of a compound according to claim
 1. 15. A method of treatment orprophylaxis of psychotic disorders or intellectual impairment disorders,which comprises administering a therapeutically effective amount of acompound according to claim
 1. 16. The method according to claim 15,wherein said psychotic disorder is Alzheimer's disease, learningdeficit, cognition deficit, attention deficit, memory loss, AttentionDeficit Hyperactivity Disorder Parkinson's disease, Huntington'sdisease, Tourette's syndrome, a neurodegenerative disorder in whichthere is loss of cholinergic synapses anxiety, schizophrenia or mania ormanic depression.
 17. A method of treatment or prophylaxis of jetlag,cessation of smoking, nicotine addiction, craving, pain, and forulcerative colitis, which comprises administering a therapeuticallyeffective amount of a compound according to claim
 1. 18. A compoundaccording to claim 1, wherein one or more of the atoms is a radioisotopeof the element.
 19. A compound according to claim 18, wherein theradioisotope is tritium.
 20. (canceled)
 21. A compound of formula IV:

wherein: M is B(OH)₂, B(OR³)₂ or SnR³ ₃; R is a substitutent selectedfrom hydrogen, C₁₋₄alkyl, C₁₋₄ halogenated alkyl, C₁₋₄ oxygenated alkyl,or halogen, and R³ is a C₁-C₆ alkyl group.
 22. A compound according toclaim 21 which is(2′R)-5′-trimethylstannyl-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine].